Upload
vocong
View
214
Download
0
Embed Size (px)
Citation preview
1 • 24
Partial AUCsPartial AUCs
Clinical Development WorkshopPrague, 15–16 October, 2013
Helmut SchützBEBAC
Helmut SchützBEBAC
Vítejte!Partial AUCs
Vítejte!Vítejte!Partial AUCsPartial AUCs
Wik
imed
iaW
ikim
edia
Com
mon
s C
omm
ons
•• 200
7 20
07 S
okol
jan
Soko
ljan
•• Cre
ativ
e C
omm
ons
Attri
butio
nC
reat
ive
Com
mon
s At
tribu
tion --
Shar
eAlik
eSh
areA
like
3.0
3.0
Unp
orte
dU
npor
ted
2 • 24
Partial AUCsPartial AUCs
Clinical Development WorkshopPrague, 15–16 October, 2013
To bear in Remembrance...To bear in Remembrance...Whenever a theory appears to youWhenever a theory appears to youas the only possible one, take this asas the only possible one, take this asa sign that you have neither undera sign that you have neither under--stood the theory nor the problemstood the theory nor the problemwhich it was intended to solve.which it was intended to solve. Karl R. PopperKarl R. Popper
Even though it’s Even though it’s appliedapplied sciencesciencewe’re dealin’ with, it still is we’re dealin’ with, it still is –– science!science!
Leslie Z. BenetLeslie Z. Benet
3 • 24
Partial AUCsPartial AUCs
Clinical Development WorkshopPrague, 15–16 October, 2013
Guidelines etc.Guidelines etc.Partial AUC (pAUC) in American guidances
‘Early Exposure’Mandatory PK metric if early onset is clinically relevant (effect or AEs) – similar to tmax for EMA
US-FDAAUCtmax,ref = pAUC truncated at population median tmax of the reference90% CI of GMR within 80–125%Canada-HPFB/TGDAUCtmax,ref = pAUC truncated at subject’s tmax of the referenceGMR within 80–125%
4 • 24
Partial AUCsPartial AUCs
Clinical Development WorkshopPrague, 15–16 October, 2013
Assumptions…Assumptions…Main assumptions in the concept of BE
(1) Similar plasma concentrations →(2) Similar concentrations at the effect site →(3) Similar clinical efficacy and safety profile.
If (1) and (2) hold, (3) can be waived →BE-study instead of therapeutic equivalence.
Concept was empirically justified in the last three decades.Is it possible that with BE shown for AUC and Cmax (tmax) we get therapeutic inequivalence?
5 • 24
Partial AUCsPartial AUCs
Clinical Development WorkshopPrague, 15–16 October, 2013
Some Doubts…Some Doubts…Concept of BE was originally developed for IR formulations and later extended to MRSeems to ‘work’, but is it also justified for more advanced technologies?
Multiphasic formulations (IR + CR parts)Osmotic pumps (OROS®)Pulsatile formulationsTargeted delivery
First doubts with CR methylphenidate → in most patients initial ‘ramp’ required for effect.
6 • 24
Partial AUCsPartial AUCs
Clinical Development WorkshopPrague, 15–16 October, 2013
Remedies?Remedies?Regulators have already some experience with partial AUCs (‘early exposure’)Discriminatory between formulations (which are passing AUC and Cmax)Open questions:
Cut-off time point data-driven (like ‘early exposure’) or set a priori?If set in the protocol, how to justify its value?
Based on pharmacology (effects)Based on PK (e.g., visible trough between phases)Different cut-offs in fasting/fed state?
7 • 24
Partial AUCsPartial AUCs
Clinical Development WorkshopPrague, 15–16 October, 2013
Guidelines etc.Guidelines etc.FDA (Zolpidem ER 2009)
Truncated AUCs (at a time point based on clinical considerations)First pAUC describes early onset, second pAUC maintenance of levels
AUC0–1.5 (~ sleep onset)AUC1.5–t (~ sleep maintenance)AUC0–∞, Cmax
pAUCs only in fasting study
FDA (Office of Generic Drugs, CDER)Draft Guidance on Zolpidem (August 2009)http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM175029.pdf
0
20
40
60
80
100
120
0 3 6 9 12 15
time (h)
zolp
idem
(ng/
mL)
Form 1A1Form 2C3
8 • 24
Partial AUCsPartial AUCs
Clinical Development WorkshopPrague, 15–16 October, 2013
Example ZolpidemExample ZolpidemFDA (Zolpidem ER 2009)
pAUC0–1.5 might be highly variable; reference-scaling?(→ EMA’s MR Draft 2013)
Midha KK and G McKayUse of Partial Area Under the Curve for BE Assessment of Products with Complex PK Profiles; a View PointMeeting of the Pharmaceutical Science and Clinical Pharmacology Advisory Committee, April 13, 2010http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AdvisoryCommitteeforPharmaceuticalScienceandClinicalPharmacology/UCM209320.pdf
37
72
N
21%26%CVintra
––113%
104 – 123%93%
85 – 103%–PE90% CI
25%27%–65%25%CVintra
9992 – 106
96%89 – 104%–
122%101 – 146%
102%96 – 110%
PE90% CI
AUC0–∞pAUC1.5–∞pAUC1.5–tpAUC0–1.5Cmaxparameter
9 • 24
Partial AUCsPartial AUCs
Clinical Development WorkshopPrague, 15–16 October, 2013
Guidelines etc.Guidelines etc.FDA (Methylphendiate SR/ER 2010)
In fasting subjects the IR’s tmax is 2 ± 0.5 h ( ± SD)Two hours is also time at which maximal response compared to placebo is achievedBy three hours, expected that 95% of patients shouldachieve maximal early onset of response (since
+ 2×SD = 95% of population)Food delays IR absorption by about one hourTruncation time point for pAUC in fed state therefore is3 + 2×0.5 h = 4 hours
BM DavitUse of Partial AUC: Case Studies and BE ApproachesMeeting of the Pharmaceutical Science and Clinical Pharmacology Advisory Committee, April 13, 2010 http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AdvisoryCommitteeforPharmaceuticalScienceandClinicalPharmacology/UCM209320.pdfFDA (Office of Generic Drugs, CDER)Draft Guidances on Methylphenidate (2010–2012)
x
x
10 • 24
Partial AUCsPartial AUCs
Clinical Development WorkshopPrague, 15–16 October, 2013
Example MethylphenidateExample MethylphenidateVarious MR formulations on the marketHybrid authorizations (PK + clinical data)Truncation time-point based on standard dosing interval of IR Ritalin (four hours)
Non-inferiority shown in clinical studiesDue to high between-subject variability of PK (high first-pass / polymorphism) and variable response dose-titration mandatoryPatients may be switched from b.i.d. IR to MRVery low intra-subject CVs of PK metrics
11 • 24
Partial AUCsPartial AUCs
Clinical Development WorkshopPrague, 15–16 October, 2013
Example MethylphenidateExample MethylphenidateApproved formulations are not interchange-able; mainly differences in pAUC0–4
1 Haessler F, Tracik F, Dietrich H, Stammer H, and J KlattA pharmacokinetic study of two modified-release methylphenidate formulations under different food conditions in healthy volunteersInt J Clin Pharmacol Ther 46(9), 466–76 (2008)
2 Schütz H, Fischer R, Großmann M, Mazur D, Leis HJ, and R AmmerLack of bioequivalence between two methylphenidate extended modified release formulations in healthy volunteersInt J Clin Pharmacol Ther 47(12), 761–9 (2009)
3 A randomized, single-center, open-label, three-way-cross-over pilot study to investigate the comparative bio-availability of two novel methylphenidate sustained-release formulations as compared to Concerta® sustained-release tablets after single oral administration in healthy male subjects (2012, unpublished)
19.082.9% ( 72.6 – 94.7%)Equasym Retard vs. Medikinet retard2
MPH MR vs. Concerta3
Ritalin LA vs. Medikinet retard1
study (fed state)
13.6110.0% ( 102.1 – 119.3%)
19.880.4% ( 73.2 – 88.2%)
CVintra (%)PE (90% CI)
12 • 24
Partial AUCsPartial AUCs
Clinical Development WorkshopPrague, 15–16 October, 2013
Example MethylphenidateExample MethylphenidateAlthough bioequivalent, variability of pAUC0–4(CV ≈20%) higher than conventional PK metrics; typical:AUC0–t 7 – 12%Cmax 10 – 15%
Fischer R, Schütz H, Grossmann M, Leis HJ, and R AmmerBioequivalence of a methylphenidate hydrochloride extended-release preparation: comparison of an intact capsule and an opened capsule sprinkled on applesauceInt J Clin Pharmacol Ther 44(3), 135–41 (2006)
Methylphenidate 20mg MR single dose fed (sprinkled vs. intact)
50
75
100
125
150
175
0 4 8 12 16
pAUC0–T (cut-off in hours)
% R
efer
ence
90% CIPE
13 • 24
Partial AUCsPartial AUCs
Clinical Development WorkshopPrague, 15–16 October, 2013
Example MethylphenidateExample MethylphenidateHigh variability of pAUC0–4 reproduciblebetween studies
Methylphenidate MR fed
0
20
40
60
80
0 4 8 12 16 20 24
pAUC0–T (cut-off in hours)
CV
intra
(%)
20/30mg SD pilot
20mg SD pivotal
20mg SD sprinkled vs. intact
60mg SD
60mg MD
14 • 24
Partial AUCsPartial AUCs
Clinical Development WorkshopPrague, 15–16 October, 2013
Guidelines etc.Guidelines etc.EMA Q&A Rev. 4 (Feb. 2012)Requirements for demonstration of bioequiva-lence for generics of biphasic modified release formulations for oral use
Phases should be separated through a cut-off time point, which needs to be pre-specified and univer-sally applied to all subjects and for both T and R. […] this cut-off time point should aim to describe the plasma concentrations in the 1st phase driven by the IR dose fraction whilst avoiding bias through an increasing contribution of the ER phase.
15 • 24
Partial AUCsPartial AUCs
Clinical Development WorkshopPrague, 15–16 October, 2013
Guidelines etc.Guidelines etc.EMA Q&A Rev. 4 (Feb. 2012)
Equivalence needs to be shown for both extent and rate of absorption (reflecting AUC and Cmax for con-ventional bioequivalence criteria), separately for both phases:
For the 1st phase, the assessment of equivalence should be based on the truncated AUC from t=0 until the cut-off time describing the immediate release dose fraction, and on Cmaxduring the first phase.For the 2nd phase, the assessment of equivalence should be based on the AUC from the cut-off time until the end of observation period, and on Cmax during the second phase.
16 • 24
Partial AUCsPartial AUCs
Clinical Development WorkshopPrague, 15–16 October, 2013
Guidelines etc.Guidelines etc.EMA Q&A Rev. 4 (Feb. 2012)
Unambigously BE of four PK metricsAUC0–T, AUCT–t, Cmax,0–T, Cmax,T–t
Practically conventional PK metrics still requestedAUC0–t, Cmax
If early onset of clinical importance, additionallytmax,0–T
Consequence: BE of up to seven PK metrics.Tough to meet…Q&A does not give suggestions on how to select the cut-off point. Reading tea-leaves: Based on PK?
17 • 24
Partial AUCsPartial AUCs
Clinical Development WorkshopPrague, 15–16 October, 2013
Guidelines etc.Guidelines etc.EMA MR Draft XXIII (March 2013)
Pre-specified truncation time point. Justification?Descriptive up to ten PK metrics (lines 787–792)
AUC0–t, AUC0–∞, Cmax, tmax,AUC0–T, AUCT–t, Cmax,0–T, Cmax,T–t, tmax,0–T, tmax,T–t
Statistical comparison (lines 800–805)AUC0–t, AUC0–∞, Cmax, AUC0–T, AUCT–t
Conventional acceptance range 80.00–125.00% or widening if CVWR >30% (replicate design)
18 • 24
Partial AUCsPartial AUCs
Clinical Development WorkshopPrague, 15–16 October, 2013
PitfallsPitfallsWhat to do if (due to deviations in sampling) a concentration was not measured at the scheduled truncation time point?
Exclude the subject from comparing the affected PK metrics. Easy & stupid.Use an estimate, i.e., interpolate linear in the increasing part or lin/log in the decreasing part of the profile.Standard in Phoenix/WinNonlin.
19 • 24
Partial AUCsPartial AUCs
Clinical Development WorkshopPrague, 15–16 October, 2013
5
10
15
20
0 2 4 6 8 10 12 14 16 18 20 22 24time (h)
conc
entra
tion
(ng/
mL)
Interpolation at cutInterpolation at cut--offoff
20 • 24
Partial AUCsPartial AUCs
Clinical Development WorkshopPrague, 15–16 October, 2013
Guidelines etc.Guidelines etc.EMA MR Draft XXIII (March 2013)
Waiving of multiple dose studies of prolonged release formulations acceptable if:
Low accumulation (single dose AUC0–τ > 90% of mean AUC0–∞ for both test and reference) andBE for additional shape parameters demonstrated.‘An early partialAUC and a terminal partialAUC separated by a predefined time point, which is usually the half of the dosage interval are recommended, unless other-wise scientifically justified.’
21 • 24
Partial AUCsPartial AUCs
Clinical Development WorkshopPrague, 15–16 October, 2013
Guidelines etc.Guidelines etc.EMA MR Draft XXIII (March 2013)
Waiving of MD studies of PR formulationsDepending on the type of formulation pAUCs might not be optimal PK metrics. Not a single publication [sic] about pAUC0–τ/2 and pAUCτ/2–τ.Alternatives
Plateau time t75% (time interval where C ≥75% of Cmax; aka Peak-Occupancy-Time POT-25)Half-Value-Duration HVD (time interval where C ≥50% of Cmax; aka Peak-Occupancy-Time POT-50)pAUC of monoexponential PK truncated at the inflection point of the curve (2×tmax)
22 • 24
Partial AUCsPartial AUCs
Clinical Development WorkshopPrague, 15–16 October, 2013
2
4
6
8
0 4 8 12 16 20 24time (h)
conc
entra
tion
(ng/
mL)
tt75%75% • HVD • 2×t• HVD • 2×tmaxmax
23 • 24
Partial AUCsPartial AUCs
Clinical Development WorkshopPrague, 15–16 October, 2013
Thank You!Thank You!Partial AUCsPartial AUCs
Open Questions?Open Questions?
Helmut SchützBEBAC
Consultancy Services forBioequivalence and Bioavailability Studies
1070 Vienna, [email protected]
24 • 24
Partial AUCsPartial AUCs
Clinical Development WorkshopPrague, 15–16 October, 2013
ReferencesReferencesEMA-CPMP/CHMP/EWP
Note for Guidance on Modified Release oral and Transdermal Dosage Forms: Section II – Pharmaco-kinetic and Clinical Evaluation (1999)Guideline on the Investigation of BE (2010)Questions & Answers: Positions on specific questions addressed to the EWP therapeutic subgroup on Pharmacokinetics (2013)Draft Guideline on the Pharmacokinetic and Clinical Evaluation of Modified Release Dosage Forms (2013)
US-FDACenter for Drug Evaluation and Research (CDER)
BA and BE Studies for Orally Administered Drug Products—General Considerations (March 2003)Bioequivalence Recommendations for Specific Products (2007–2013):Guidance on Zolpidem (Oct 2011)Draft Guidances on Methylphenidate(2010–2012)
Docket No. FDA-2007-P-0182 – Sanofi Aventis U.S. Inc. / ANDA Suitability Petition for NDA 21-774 Ambien CR (Zolpidem tartrate), 13 Oct 2010
Docket No. 2004P-0139 – McNeil Consumer & Specialty Pharmaceuticals/Approval of Generic Version of Concerta (methylphenidate HCl extended-release tablets are both bio-equivalent and clinically equivlent to the innovator product), 19 Mar 2004Steinijans et al.Shape Analysis in Single- and Multiple-Dose Studies of Modified Release Products, in: Bio-International 2medpharm Scientific Publishers 1995, Stuttgart, 193–206Endrényi et al.The duration of measuring partial AUCs for the assessment of bioequivalencePharm Res 15(3), 399–404 (1998)Endrényi and TóthfalusiMetrics for the Evaluation of Bioequivalence of Modified-Release FormulationsAPPS J 14(4), 321–5 (2012) DOI: 10.1208/s12248-012-9396-8Zirkelbach JF, Jackson AJ, Wang Y, and DJ SchuirmannUse of Partial AUC (PAUC) to Evaluate Bioequivalence—A Case Study with Complex Absorption: MethylphenidatePharm Res 30(1), 191–202 (2013)DOI: 10.1007/s11095-012-0862-x